1. Field of the Invention
This invention is directed to novel quinazolinone compounds which are useful as local anesthetics. This invention is also directed to pharmaceutical compositions comprising such compounds; methods of using such compounds as, for example, local anesthetics; and processes and intermediates for preparing such compounds.
2. State of the Art
Local anesthetics are widely used for preventing and treating various types of pain. However, currently available local anesthetics have a relatively short duration of action and must be repeatedly or continuously administered to provide prolonged pain relief. As a result, such agents are generally unsatisfactory for treating post-surgical or chronic pain. See, for example, Paul J. Kuzma et al., xe2x80x9cProgress in the Development of Ultra-Long-Acting Local Anestheticsxe2x80x9d Regional Anesthesia 1997, 22(6), 543-551. Accordingly, a significant need exists for long-acting local anesthetics to provide effective post-operative analgesia and treatment for chronic pain.
The present invention provides novel quinazolinone compounds which are useful as local anesthetics. Among other properties, compounds of this invention have been found to provide a longer duration of analgesia compared to currently available local anesthetics.
Accordingly, in one of its composition aspects, this invention provides a compound of formula I: 
wherein
R1 is selected from the group consisting of hydrogen, C1-6 alkyl and C1-6 alkoxy;
R2 is selected from the group consisting of hydrogen, C1-6 alkyl and C1-6 alkoxy;
R3 is hydrogen or C1-6 alkyl;
R4 is hydrogen or C1-6 alkyl;
R5 is hydrogen or C1-6 alkyl;
each R6 is independently selected from the group consisting of C1-6 alkyl and C1-6 alkoxy;
n is an integer from 0 to 3;
and pharmaceutically acceptable salts and stereoisomers thereof.
This invention is also directed to intermediates useful for preparing compounds of formula I. Accordingly, in another of its composition aspects, this invention provides a compound of formula II: 
wherein R4, R5, R6 and n are as defined herein, or a salt thereof, which compounds are useful as intermediates for preparing compounds of formula I.
Additionally, in still another of its composition aspects, this invention provides a compound of formula III: 
wherein R1, R2 and R3 are as defined herein, or a salt thereof, which compounds are also useful as intermediates for preparing compounds of formula I.
In yet another of its composition aspects, this invention provides a pharmaceutical composition comprising a pharamaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
The compounds of formula I have been discovered to inhibit or modulate voltage-gated sodium channels associated with nerve conduction. Additionally, the compounds of this invention produce local anesthesia or analgesia when administered to a mammal. Therefore, among other properties, the compounds of formula I are useful as local anesthetics.
Accordingly, in one of its method aspects, this invention is directed to a method for producing local anesthesia or analgesia in a mammal, the method comprising administering to a mammal a pharmaceutical composition comprising a pharamaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
Additionally, in another of its method aspects, this invention provides a method for treating a disease or medical condition associated with or modulated by a volatge-gated sodium channel, the method comprising administering to a patient in need of treatment a pharmaceutical composition comprising a pharamaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
This invention is also directed to processes for preparing compounds of formula I. Accordingly, in another of its method aspects, this invention is directed to a process for preparing a compound of formula I, the process comprising contacting a compound of formula II above with a compound of formula IV: 
wherein R1, R2 and R3 are as defined herein; and X is a leaving group; to provide a compound of formula I. Additionally, in another of its composition aspects, this invention is directed to a compound of formula I prepared by this process.
In still another of its method aspects, this invention is directed to another process for preparing a compound of formula I, the process comprising contacting a compound of formula III with a compound of formula V: 
wherein R4, R5, R6 and n are as defined herein, and X is a leaving group; to provide a compound of formula I. This invention is also directed to a compound of formula I prepared by this process.
In yet another of its method aspects, this invention is directed to the use of a compound of formula I for the manufacture of a medicament. Preferably, the medicament is used to produce local anesthesia or analgesia in a mammal.